Optimized OPA1 Isoforms 1 and 7 Provide Therapeutic Benefit in Models of Mitochondrial Dysfunction

Maloney, Daniel; Chadderton, Naomi; Millington‐Ward, Sophia; Palfi, Arpad; Shortall, Ciara; O’Byrne, James J.; Cassidy, Lorraine; Keegan, David; Humphries, Peter; Kenna, Paul F.; Farrar, G. Jane

doi:10.3389/fnins.2020.571479

Cited by 12 publications

(12 citation statements)

References 69 publications

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“…Activation of OMA1 in mouse heart leads to mitochondrial fragmentation and disrupted metabolism, causing dilated cardiomyopathy and heart failure (Wai et al, 2015), while genetic ablation of OMA1 prevents OPA1 cleavage, delaying neuronal apoptosis in a murine neurodegeneration model (Korwitz et al, 2016), as well as mouse models of heart failure (Acin-Perez et al, 2018). Consistent with this, OMA1 silencing confers increased cell proliferation and migration in patient-derived metastatic cancer cells (Daverey et al, 2019), while adenoviral delivery of OPA1 rescues mitochondrial dysfunction in in vitro models (Maloney et al, 2020). Taken together, these findings suggest that OMA1's role in controlling stress-sensitive OPA1 cleavage has crucial importance to cellular fate through modulation of apoptosis.…”

Section: Oma1 Opa1 and Cellular Apoptosismentioning

confidence: 73%

Mitochondrial OMA1 and OPA1 as Gatekeepers of Organellar Structure/Function and Cellular Stress Response

Gilkerson

Torre

Vallier

2021

Front. Cell Dev. Biol.

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Mammalian mitochondria are emerging as a critical stress-responsive contributor to cellular life/death and developmental outcomes. Maintained as an organellar network distributed throughout the cell, mitochondria respond to cellular stimuli and stresses through highly sensitive structural dynamics, particularly in energetically demanding cell settings such as cardiac and muscle tissues. Fusion allows individual mitochondria to form an interconnected reticular network, while fission divides the network into a collection of vesicular organelles. Crucially, optic atrophy-1 (OPA1) directly links mitochondrial structure and bioenergetic function: when the transmembrane potential across the inner membrane (ΔΨm) is intact, long L-OPA1 isoforms carry out fusion of the mitochondrial inner membrane. When ΔΨm is lost, L-OPA1 is cleaved to short, fusion-inactive S-OPA1 isoforms by the stress-sensitive OMA1 metalloprotease, causing the mitochondrial network to collapse to a fragmented population of organelles. This proteolytic mechanism provides sensitive regulation of organellar structure/function but also engages directly with apoptotic factors as a major mechanism of mitochondrial participation in cellular stress response. Furthermore, emerging evidence suggests that this proteolytic mechanism may have critical importance for cell developmental programs, particularly in cardiac, neuronal, and stem cell settings. OMA1’s role as a key mitochondrial stress-sensitive protease motivates exciting new questions regarding its mechanistic regulation and interactions, as well as its broader importance through involvement in apoptotic, stress response, and developmental pathways.

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Section: Oma1 Opa1 and Cellular Apoptosismentioning

confidence: 73%

Mitochondrial OMA1 and OPA1 as Gatekeepers of Organellar Structure/Function and Cellular Stress Response

Gilkerson

Torre

Vallier

2021

Front. Cell Dev. Biol.

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“…Rotenone is a lipophilic, naturally occurring compound acting as a strong inhibitor of complex I of the mitochondrial respiratory chain [ 122 ]. Using the murine model of rotenone-induced optic neuropathy, Maloney et al the reported therapeutic benefit of OPA1 isoform 1 and 7 delivered by AAV-2 via IVT route [ 123 ].…”

Section: Gt Of Diseases Caused By Ndna Mutationsmentioning

confidence: 99%

Current advances in gene therapy of mitochondrial diseases

et al. 2022

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Mitochondrial diseases (MD) are a heterogeneous group of multisystem disorders involving metabolic errors. MD are characterized by extremely heterogeneous symptoms, ranging from organ-specific to multisystem dysfunction with different clinical courses. Most primary MD are autosomal recessive but maternal inheritance (from mtDNA), autosomal dominant, and X-linked inheritance is also known. Mitochondria are unique energy-generating cellular organelles designed to survive and contain their own unique genetic coding material, a circular mtDNA fragment of approximately 16,000 base pairs. The mitochondrial genetic system incorporates closely interacting bi-genomic factors encoded by the nuclear and mitochondrial genomes. Understanding the dynamics of mitochondrial genetics supporting mitochondrial biogenesis is especially important for the development of strategies for the treatment of rare and difficult-to-diagnose diseases. Gene therapy is one of the methods for correcting mitochondrial disorders. Graphical Abstract

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“…OPA1 plays essential roles in mitochondria, including remodeling cristae morphology, inner mitochondrial membrane fusion, efficiency of oxidative phosphorylation, and mitochondrial genome maintenance. Under normal conditions, there is a stoichiometric balance between L-Opa1 and S-Opa1, and each function is performed by specific isoforms [6].…”

Section: Introductionmentioning

confidence: 99%

OPA1 Dominant Optic Atrophy: Diagnostic Approach in the Pediatric Population

Arruti

Rodríguez-Solana

Nieves-Moreno

et al. 2023

CIMB

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A clinical and genetic study was conducted with pediatric patients and their relatives with optic atrophy 1 (OPA1) mutations to establish whether there is a genotype–phenotype correlation among the variants detected within and between families. Eleven children with a confirmed OPA1 mutation were identified during the study period. The main initial complaint was reduced visual acuity (VA), present in eight patients of the cohort. Eight of eleven patients had a positive family history of optic atrophy. The mean visual acuity at the start of the study was 0.40 and 0.44 LogMAR in the right and left eye, respectively. At the end of the study, the mean visual acuity was unchanged. Optical coherence tomography during the first visit showed a mean retinal nerve fiber layer thickness of 81.6 microns and 80.5 microns in the right and left eye, respectively; a mean ganglion cell layer of 52.5 and 52.4 microns, respectively, and a mean central macular thickness of 229.5 and 233.5 microns, respectively. The most common visual field defect was a centrocecal scotoma, and nine out of eleven patients showed bilateral temporal disc pallor at baseline. Sequencing of OPA1 showed seven different mutations in the eleven patients, one of which, NM_130837.3: c.1406_1407del (p.Thr469LysfsTer16), has not been previously reported. Early diagnosis of dominant optic atrophy is crucial, both for avoiding unnecessary consultations and/or treatments and for appropriate genetic counseling.

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Optimized OPA1 Isoforms 1 and 7 Provide Therapeutic Benefit in Models of Mitochondrial Dysfunction

Cited by 12 publications

References 69 publications

Mitochondrial OMA1 and OPA1 as Gatekeepers of Organellar Structure/Function and Cellular Stress Response

Mitochondrial OMA1 and OPA1 as Gatekeepers of Organellar Structure/Function and Cellular Stress Response

Current advances in gene therapy of mitochondrial diseases

OPA1 Dominant Optic Atrophy: Diagnostic Approach in the Pediatric Population

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